US7094899B2 - Vitreous form of known bradykinin antagonist - Google Patents
Vitreous form of known bradykinin antagonist Download PDFInfo
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- US7094899B2 US7094899B2 US10/301,614 US30161402A US7094899B2 US 7094899 B2 US7094899 B2 US 7094899B2 US 30161402 A US30161402 A US 30161402A US 7094899 B2 US7094899 B2 US 7094899B2
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- UDUDZLSOWDCUNM-BUHFOSPRSA-N CC(=O)NC1=NC=C(/C=C/OCNCC(=O)N(C)C2=C(Cl)C(COC3=C4N=C(C)C=CC4=CC=C3)=C(Cl)C=C2)C=C1 Chemical compound CC(=O)NC1=NC=C(/C=C/OCNCC(=O)N(C)C2=C(Cl)C(COC3=C4N=C(C)C=CC4=CC=C3)=C(Cl)C=C2)C=C1 UDUDZLSOWDCUNM-BUHFOSPRSA-N 0.000 description 1
- 0 Cc1nc(c(OCc(c(Cl)c(cc2)N(C)*C*C=C[C@@]3C=CC(*)=NC3)c2Cl)ccc2)c2cc1 Chemical compound Cc1nc(c(OCc(c(Cl)c(cc2)N(C)*C*C=C[C@@]3C=CC(*)=NC3)c2Cl)ccc2)c2cc1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- the present invention relates to a vitreous form of 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (hereinafter referred to as FR173657) and a pharmaceutical composition comprising it.
- FR173657 is a compound of the following formula [I], and is disclosed in Japanese Patent Laid-Open No. 2780/1995 or in Journal of Medicinal Chemistry, 1998, Vol. 41, No. 21, 4062–4079.
- FR173657 possesses an excellent activity as a bradykinin antagonist.
- FR173657 described in the laid-open specification mentioned above is in amorphous form as obtained through solidification in a solvent. This amorphous form has a melting point broadly ranging between 133 and 139° C., and its solid stability is poor. Therefore, this is problematic in that products of quality sufficiently stable to be acceptable as medicines are difficult to produce and supply.
- FR173657 involves crystallographic polymorphism, of which crystal hydrates having high purity and good solid stability and easy to handle for formulation into medicines, more preferably three types of crystals referred to as crystal type A, crystal type B and crystal type C, have been found (Japanese Patent Laid-Open No. 316677/1998).
- crystal type A is problematic in that it is often contaminated with the crystal type C, making impossible production with stable quality.
- the crystal type B is the most stable and there is no problem in producing it, but is problematic in that its releasability is much inferior to that of the crystal type A.
- the crystal type C is also problematic in that its solid stability is inferior to that of the crystal type B and its releasability is inferior to that of the crystal type A. Therefore, further studies for finding out another form of FR173657 more suitable to medicines are needed.
- FIG. 1 Infrared absorption spectrum of the vitreous form of FR173657
- FIG. 2 Profile of the vitreous form of FR173657 in differential scanning calorimetry (DSC)
- FIG. 3 Infrared absorption spectrum of the crystal of FR173657 hydrate (crystal type A)
- FIG. 4 Infrared absorption spectrum of the crystal of FR173657 hydrate (crystal type B)
- FIG. 5 Infrared absorption spectrum of the crystal of FR173657 hydrate (crystal type C)
- FIG. 6 Solubility test results in Example 8.
- the “vitreous form” indicates an amorphous solid substance that is in a vitreous state, and this is obtained by cooling a liquid substance in a molten state without crystallizing it.
- amorphous form indicates an amorphous solid substance that is in a vitreous state, and this is obtained by cooling a liquid substance in a molten state without crystallizing it.
- amorphous form indicates other amorphous solid substances not in vitreous state.
- the vitreous form of FR173657 has the following physicochemical properties.
- DSC Differential scanning calorimetry
- the vitreous form of FR173657 of the invention can be produced by heating an amorphous form, crystalline form, or a mixture thereof of FR173657 or its solvate [i.e. hydrate, ethanolate, etc.] at a temperature not lower than its melting point, followed by cooling it in a molten state.
- amorphous form, crystalline form, or a mixture thereof of FR173657 or its solvate i.e. hydrate, ethanolate, etc.
- the melting point varies depending on the condition of the FR173657 or its solvate to be processed (whether it is amorphous or crystalline, or the ratio of the mixture thereof), but any temperature at which the initial stage FR173657 or its solvate melts is suitable for this process.
- the initial stage FR173657 or its solvate melts in the range of about 130 to 220° C.
- the method of heating the initial stage FR173657 or its solvate to the temperature not lower than its melting point is not specifically limited.
- the starting FR173657 or its solvate is fed into a container under cooling, at ambient temperature or under heating, and then heated up to a temperature not lower than its melting point so as to melt it; or it is fed into a container having been heated at around its melting point or higher so as to melt it. After having been thus melted, this may be immediately cooled. Preferably, however, this is kept in a molten state for about 20 to 40 minutes, and then cooled.
- the cooling method is not specifically limited. In general, the heated system is simply left to cool by itself.
- the obtained vitreous form of FR173657 may be ground or milled mechanically for manufacturing pharmaceutical preparations.
- the initial stage FR173657 or its solvate may be in amorphous, crystalline or a mixture thereof.
- Crystal of a solvate of FR173657 may be prepared by any conventional methods such as a method comprising stirring FR173657 in a solvent under warming or heating and thereafter cooling it to give a crystalline precipitate, a method comprising the dissolution of FR173657 in a solvent in an acidic condition followed by adding thereto a base and optionally water or a hydrous solvent to neutralize it thereby giving a crystalline precipitate, a method comprising the exposure crystal of FR173657 to steam or to a vapor of an organic solvent, a method comprising any of these methods in combination, or the like, in which FR173657 can be obtained as an amorphous form according to a known method, for example, described in Japanese Patent Laid-Open No. 2780/1995.
- the solvent to be used for precipitating the crystal may include water; conventional organic solvents such as alcohols, for example, methanol, ethanol, isopropyl alcohol, etc., acetone, N,N-dimethylformamide, dioxane, tetrahydrofuran, ethyl acetate, acetonitrile, dimethylsulfoxide, or the like; and a mixture thereof. More preferred are hydrous alcohols such as hydrous methanol, hydrous ethanol, etc.; hydrous acetone; and mixed solvents of water and an organic solvent such as a combination of water and ethyl acetate.
- alcohols for example, methanol, ethanol, isopropyl alcohol, etc.
- acetone N,N-dimethylformamide
- dioxane tetrahydrofuran
- ethyl acetate acetonitrile
- dimethylsulfoxide or the like
- hydrous alcohols such as hydrous methanol,
- crystal type A, crystal type B and crystal type C mentioned above can also be prepared, for example, according to the methods described in the following Preparations or similar manners thereto.
- the vitreous form of FR173657 of the invention possesses strong activity as a bradykinin antagonist, and is useful for the treatment and/or the prevention of bradykinin or its analogues mediated diseases, such as allergy, inflammation, autoimmune disease, shock, pain, or the like in human being or animals.
- the vitreous form of FR173657 of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral; parenteral such as intravenous, intramuscular, subcutaneous or intraarticular; external such as topical, enteral, intrarectal, transvaginal, inhalant, ophthalmic, nasal or hypoglossal administration.
- the pharmaceutical preparations may be capsules, tablets, dragees, granules, suppositories, solution, lotion, suspension, emulsion, ointment, gel, cream, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
- the dosage of the vitreous form of FR173657 will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the vitreous form of FR173657 may be effective for preventing and/or treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
- vitreous form crystallizes extremely rapidly and its stability is poor.
- vitreous form of FR173657 of the invention neither crystallizes nor decomposes at all even under heat or in moisture or through physical treatment, and is quite stable.
- the vitreous form of FR173657 of the invention has higher purity and better solid stability, as compared with known FR173657, and has higher solubility and better releasability than crystallographic polymorphic FR173657. Therefore, it is useful for producing and supplying FR173657 products whose quality is stable enough to be suitable for medicines.
- FR173657 (7 g) was added to methanol (720 ml) at 60° C., and stirred under reflux for 5 minutes. The mixture was cooled to below 30° C., and stirred for 2 hours at the range of 20 to 30° C. to give a precipitate. The mixture containing crystalline precipitate was filtered, and the obtained crystalline precipitate was washed with methanol (14 ml) and dried in vacuo at 40° C. to give a crude anhydrous crystal of FR173657 (6.3 g) (hereinafter referred to as crude FR173657 crystal). The crystal contained about 5% methanol.
- a tray was fitted in a hot air-circulating thermostat, baked at 230° C. empty, and then cooled below 100° C. This was again heated to be at a fixed temperature of 160° C. After the fixed temperature of the tray was confirmed, the crystal of FR173657 hydrate (crystal type A) was uniformly spread on the tray and heated thereon. After the temperature of the substance reached 160° C., this was kept as it was for 30 minutes, and then left to cool to give a vitreous form of FR173657.
- a tray was fitted in a hot air-circulating thermostat, baked at 230° C. empty, and then cooled below 100° C. This was again heated to be at a fixed temperature of 220° C. After the fixed temperature of the tray was confirmed, the crystal of FR173657 hydrate (crystal type B) was uniformly spread on the tray and heated thereon. After the temperature of the substance reached 220° C., this was kept as it was for 30 minutes, and then left to cool to give a vitreous form of FR173657.
- a tray was fitted in a hot air-circulating thermostat, baked at 230° C. empty, and then cooled below 100° C. This was again heated to be at a fixed temperature of 160° C. After the fixed temperature of the tray was confirmed, the crystal of FR173657 hydrate (crystal type C) was uniformly spread on the tray and heated thereon. After the temperature of the substance reached 160° C., this was kept as it was for 30 minutes, and then left to cool to give a vitreous form of FR173657.
- a tray was fitted in a hot -air-circulating thermostat, baked at 230° C. empty, and then cooled below 100° C. This was again heated to be at a fixed temperature of 160° C. After the fixed temperature of the tray was confirmed, the crystal of FR173657 hydrate (mixture of crystal type A and crystal type C) was uniformly spread on the tray and heated thereon. After the temperature of the substance reached 160° C., this was kept as it was for 30 minutes, and then left to cool to give a vitreous form of FR173657.
- the above components were granulated and tabletted in a conventional manner to prepare bare tablets, which were coated with a film in a conventional manner to obtain film-coated tablets containing the vitreous form of FR173657.
- Vitreous form of FR173657 15 mg D-mannitol proper quantity Low-substituted hydroxypropyl 10 mg cellulose Crystalline cellulose 20 mg Hydroxypropyl cellulose 2 mg Magnesium stearate 1 mg
- the above components were granulated and tabletted in a conventional manner to prepare bare tablets, which were coated with a film in a conventional manner to obtain film-coated tablets containing the vitreous form of FR173657.
- the above components were granulated and tabletted in a conventional manner to prepare bare tablets, which were coated with a film in a conventional manner to give film-coated tablets containing the vitreous form of FR173657.
- a solubility test was performed in conformity with the Japanese Pharmacopoeia(JP) XIII dissolution test, paddle method.
- As the test solution 900 ml of distilled water was used. The paddle speed was set to 50 rpm.
- the vitreous form of FR173657 (100 g) was added to the test solution and 10 ml aliquots of the test solution were taken as samples in each measurement. Each sample was filtered through a 0.45 ⁇ m filter and analyzed by high-performance liquid chromatography.
- crystal type A As a control, crystal type A, crystal type B, crystal type C and a mixture of crystal types A and C of FR173657 hydrate were used.
- Test results are shown in FIG. 6 .
- vitreous form of FR173657 of the invention has higher solubility any crystallographic polymorphic FR173657.
- vitreous form of FR173657 of the invention neither crystallizes nor decomposes at all even under heat or in moisture or through physical treatment, and is quite stable under long-term storage.
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Abstract
This invention relates to a vitreous form of 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (FR173657). This vitreous form has good solid stability and, therefor, is useful for producing and supplying FR173657 products whose quality is stable enough to be suitable for medicines.
Description
The present application is a continuation of U.S. Ser. No. 09/807,421, filed on Apr. 20, 2001. now U.S. Pat. No. 6,509,468, which is a National Stage of PCT/JP99/05519, filed on Oct. 7, 1999, which claims priority to Japanese patent application JP 10-299252, filed on Oct. 21, 1998.
The present invention relates to a vitreous form of 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (hereinafter referred to as FR173657) and a pharmaceutical composition comprising it.
FR173657 is a compound of the following formula [I], and is disclosed in Japanese Patent Laid-Open No. 2780/1995 or in Journal of Medicinal Chemistry, 1998, Vol. 41, No. 21, 4062–4079.
This possesses activity as a bradykinin antagonist, and is useful as an agent for the prevention and/or the treatment of, for example, allergy, inflammation, autoimmune disease, shock, pain, or the like.
FR173657 possesses an excellent activity as a bradykinin antagonist. However, FR173657 described in the laid-open specification mentioned above is in amorphous form as obtained through solidification in a solvent. This amorphous form has a melting point broadly ranging between 133 and 139° C., and its solid stability is poor. Therefore, this is problematic in that products of quality sufficiently stable to be acceptable as medicines are difficult to produce and supply.
FR173657 involves crystallographic polymorphism, of which crystal hydrates having high purity and good solid stability and easy to handle for formulation into medicines, more preferably three types of crystals referred to as crystal type A, crystal type B and crystal type C, have been found (Japanese Patent Laid-Open No. 316677/1998). However, though having good solid stability and releasability, the crystal type A is problematic in that it is often contaminated with the crystal type C, making impossible production with stable quality. The crystal type B is the most stable and there is no problem in producing it, but is problematic in that its releasability is much inferior to that of the crystal type A. The crystal type C is also problematic in that its solid stability is inferior to that of the crystal type B and its releasability is inferior to that of the crystal type A. Therefore, further studies for finding out another form of FR173657 more suitable to medicines are needed.
Given that situation, we, the present inventors have assiduously studied FR173657, and, as a result, have found a vitreous form of FR173657 having high purity, good solid stability, good solubility and good releasability and capable of production with stable quality, and have completed the present invention.
The “vitreous form” indicates an amorphous solid substance that is in a vitreous state, and this is obtained by cooling a liquid substance in a molten state without crystallizing it. In this specification, for convenience, other amorphous solid substances not in vitreous state are referred to as “amorphous form”.
The vitreous form of FR173657 has the following physicochemical properties.
Conditions for Measurement:
Infrared absorption spectrum:
-
- According to the Nujol method
Differential scanning calorimetry (DSC):
-
- heating rate: 10° C./minute
Physicochemical Properties of Vitreous Form of FR173657
- heating rate: 10° C./minute
(a) Specific peaks in infrared absorption spectrum:
-
- 1684, 1662, 1524, 1236 and 836 cm−1
- Infrared absorption spectrum is shown in
FIG. 1 .
(b) Differential scanning calorimetry (DSC):
-
- Endothermic peak due to glass transition appears at around 115 to 122° C. (with its peak top appearing at around 126 to 128° C.).
- Profile in differential scanning calorimetry (DSC) is shown in
FIG. 2 .
The vitreous form of FR173657 of the invention can be produced by heating an amorphous form, crystalline form, or a mixture thereof of FR173657 or its solvate [i.e. hydrate, ethanolate, etc.] at a temperature not lower than its melting point, followed by cooling it in a molten state.
The melting point varies depending on the condition of the FR173657 or its solvate to be processed (whether it is amorphous or crystalline, or the ratio of the mixture thereof), but any temperature at which the initial stage FR173657 or its solvate melts is suitable for this process. In general, the initial stage FR173657 or its solvate melts in the range of about 130 to 220° C.
The method of heating the initial stage FR173657 or its solvate to the temperature not lower than its melting point is not specifically limited. For example, the starting FR173657 or its solvate is fed into a container under cooling, at ambient temperature or under heating, and then heated up to a temperature not lower than its melting point so as to melt it; or it is fed into a container having been heated at around its melting point or higher so as to melt it. After having been thus melted, this may be immediately cooled. Preferably, however, this is kept in a molten state for about 20 to 40 minutes, and then cooled.
The cooling method is not specifically limited. In general, the heated system is simply left to cool by itself.
The obtained vitreous form of FR173657 may be ground or milled mechanically for manufacturing pharmaceutical preparations.
The initial stage FR173657 or its solvate may be in amorphous, crystalline or a mixture thereof. Crystal of a solvate of FR173657 may be prepared by any conventional methods such as a method comprising stirring FR173657 in a solvent under warming or heating and thereafter cooling it to give a crystalline precipitate, a method comprising the dissolution of FR173657 in a solvent in an acidic condition followed by adding thereto a base and optionally water or a hydrous solvent to neutralize it thereby giving a crystalline precipitate, a method comprising the exposure crystal of FR173657 to steam or to a vapor of an organic solvent, a method comprising any of these methods in combination, or the like, in which FR173657 can be obtained as an amorphous form according to a known method, for example, described in Japanese Patent Laid-Open No. 2780/1995.
The solvent to be used for precipitating the crystal may include water; conventional organic solvents such as alcohols, for example, methanol, ethanol, isopropyl alcohol, etc., acetone, N,N-dimethylformamide, dioxane, tetrahydrofuran, ethyl acetate, acetonitrile, dimethylsulfoxide, or the like; and a mixture thereof. More preferred are hydrous alcohols such as hydrous methanol, hydrous ethanol, etc.; hydrous acetone; and mixed solvents of water and an organic solvent such as a combination of water and ethyl acetate.
The crystal type A, crystal type B and crystal type C mentioned above can also be prepared, for example, according to the methods described in the following Preparations or similar manners thereto.
The vitreous form of FR173657 of the invention possesses strong activity as a bradykinin antagonist, and is useful for the treatment and/or the prevention of bradykinin or its analogues mediated diseases, such as allergy, inflammation, autoimmune disease, shock, pain, or the like in human being or animals.
For therapeutic purpose, the vitreous form of FR173657 of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral; parenteral such as intravenous, intramuscular, subcutaneous or intraarticular; external such as topical, enteral, intrarectal, transvaginal, inhalant, ophthalmic, nasal or hypoglossal administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, suppositories, solution, lotion, suspension, emulsion, ointment, gel, cream, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
While the dosage of the vitreous form of FR173657 will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the vitreous form of FR173657 may be effective for preventing and/or treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
In general, it is said that a vitreous form crystallizes extremely rapidly and its stability is poor. However, it has been verified that the vitreous form of FR173657 of the invention neither crystallizes nor decomposes at all even under heat or in moisture or through physical treatment, and is quite stable.
The vitreous form of FR173657 of the invention has higher purity and better solid stability, as compared with known FR173657, and has higher solubility and better releasability than crystallographic polymorphic FR173657. Therefore, it is useful for producing and supplying FR173657 products whose quality is stable enough to be suitable for medicines.
The invention is explained more concretely by the following Preparations and Examples, which, however, are not intended to restrict the scope of the invention.
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), (E)-3-(6-acetamidopyridin-3-yl)acrylic acid (56.1 mg) and N,N-dimethylformamide (2 ml) were added 1-hydroxybenzotriazole (43.4 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (56.9 mg) in a nitrogen stream at 0° C., and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into water, and extracted with chloroform. The organic layer was washed with an aqueous solution of saturated sodium hydrogencarbonate, water and brine successively, and dried over magnesium sulfate, and thereafter the solvent was removed under reduced pressure. The residue was purified by preparative thin-layer chromatography (methanol:dichloromethane=1:10, v/v), and solidified with diethyl ether and ethyl acetate to give 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2methylquinoline (FR173657) (78.8 mg) as a grayish white solid.
mp: 133–139° C. NMR (CDCl3, δ): 2.22 (3H, s), 2.74 (3H, s), 3.27 (3H, s), 3.67 (1H, dd, J=16.5, 5.5 Hz), 3.96 (1H, dd, J=16.5, 5.5 Hz), 5.62 (1H, d, J=11.0 Hz), 5.67 (1H, d, J=11.0 Hz), 6.46 (1H, d, J=16.0 Hz), 6.73 (1H, br t, J=5.5 Hz), 7.21–7.33 (3H, m), 7.38–7.51 (3H, m), 7.52 (1H, d, J=16.0 Hz), 7.82 (1H, dd, J=8.5, 1.5 Hz), 8.03 (1H, d, J=8.5 Hz), 8.13–8.25 (2H, m), 8.33 (1H, d, J=1.5 Hz)
FR173657 (7 g) was added to methanol (720 ml) at 60° C., and stirred under reflux for 5 minutes. The mixture was cooled to below 30° C., and stirred for 2 hours at the range of 20 to 30° C. to give a precipitate. The mixture containing crystalline precipitate was filtered, and the obtained crystalline precipitate was washed with methanol (14 ml) and dried in vacuo at 40° C. to give a crude anhydrous crystal of FR173657 (6.3 g) (hereinafter referred to as crude FR173657 crystal). The crystal contained about 5% methanol.
To a mixture of the crude FR173657 crystal (100 g) and pure water (500 ml) was added concentrated hydrochloric acid (28.1 ml) with stirring at below 10° C. to dissolve the crystal. Carbon powder (5 g) was added thereto, and the mixture was stirred for 2.5 hours. The carbon powder was filtered off, and washed with pure water (200 ml) and concentrated hydrochloric acid (1.4 ml). The resulting filtrate was added to a mixture of acetone (700 ml) and triethylamine (35.87 g) at 55° C., stirred at the same temperature for 5 minutes, and then refluxed for 20 minutes. After the mixture was cooled to 40° C., the crystal was collected by filtration. The crystal was washed with 50% acetone, and dried in vacuo to give a crystal of FR173657 hydrate (crystal type A) (88.7 g).
-
- Infrared absorption spectrum
- As shown in
FIG. 3
Preparation 4
- As shown in
- Infrared absorption spectrum
To a mixture of the crude FR173657 crystal (50 g) and pure water (250 ml) was added concentrated hydrochloric acid (14.1 ml) with stirring at 5° C. to dissolve the crystal. Carbon powder (2.5 g) was added thereto, and the mixture was stirred for 30 minutes. The carbon powder was filtered off, washed with diluted hydrochloric acid. The resulting filtrate was added to a mixture of ethyl acetate (350 ml) and triethylamine (17.93 g) at 70° C., and stirred under reflux for 2 hours. After the mixture was cooled to 20° C. and then stirred at the same temperature for additional 2 hours, the resulting crystal was collected by filtration. The crystal was washed with ethyl acetate (100 ml) and pure water (100 ml), and dried in vacuo at 40° C. to give a crystal of FR173657 hydrate (crystal type B) (44.51 g).
-
- Infrared absorption spectrum
- As shown in
FIG. 4
Preparation 5
- As shown in
- Infrared absorption spectrum
To a mixture of the crude FR173657 crystal (260 g) and pure water (1300 ml) was added concentrated hydrochloric acid (73 ml) with stirring for 10 minutes at 5° C. to dissolve the crystal. After having been filtered, the residue was washed with diluted hydrochloric acid. The resulting filtrate was dropwise added to a mixture of acetone (6500 ml), pure water (4680 ml) and triethylamine (93.3 g) over a period of 30 minutes at 20° C., to which was added a seed crystal type C (26 mg). The resulting mixture was stirred at the same temperature for 2.5 hours, then cooled to 3° C., and further stirred for 2 hours. The crystal was collected by filtration, washed with 50 % acetone (520 ml), and dried in vacuo at 40° C. to give a crystal of FR173657 hydrate (crystal type C) (236.68 g).
-
- Infrared absorption spectrum
- As shown in
FIG. 5
- As shown in
- Infrared absorption spectrum
A tray was fitted in a hot air-circulating thermostat, baked at 230° C. empty, and then cooled below 100° C. This was again heated to be at a fixed temperature of 160° C. After the fixed temperature of the tray was confirmed, the crystal of FR173657 hydrate (crystal type A) was uniformly spread on the tray and heated thereon. After the temperature of the substance reached 160° C., this was kept as it was for 30 minutes, and then left to cool to give a vitreous form of FR173657.
-
- Infrared absorption spectrum
- As shown in
FIG. 1
- As shown in
- Profile in differential scanning calorimetry (DSC)
- As shown in
FIG. 2
- As shown in
- Infrared absorption spectrum
A tray was fitted in a hot air-circulating thermostat, baked at 230° C. empty, and then cooled below 100° C. This was again heated to be at a fixed temperature of 220° C. After the fixed temperature of the tray was confirmed, the crystal of FR173657 hydrate (crystal type B) was uniformly spread on the tray and heated thereon. After the temperature of the substance reached 220° C., this was kept as it was for 30 minutes, and then left to cool to give a vitreous form of FR173657.
Its infrared absorption spectrum and its profile in differential scanning calorimetry (DSC) were both the same as those of the vitreous form obtained in Example 1.
A tray was fitted in a hot air-circulating thermostat, baked at 230° C. empty, and then cooled below 100° C. This was again heated to be at a fixed temperature of 160° C. After the fixed temperature of the tray was confirmed, the crystal of FR173657 hydrate (crystal type C) was uniformly spread on the tray and heated thereon. After the temperature of the substance reached 160° C., this was kept as it was for 30 minutes, and then left to cool to give a vitreous form of FR173657.
Its infrared absorption spectrum and its profile in differential scanning calorimetry (DSC) were both the same as those of the vitreous form obtained in Example 1.
A tray was fitted in a hot -air-circulating thermostat, baked at 230° C. empty, and then cooled below 100° C. This was again heated to be at a fixed temperature of 160° C. After the fixed temperature of the tray was confirmed, the crystal of FR173657 hydrate (mixture of crystal type A and crystal type C) was uniformly spread on the tray and heated thereon. After the temperature of the substance reached 160° C., this was kept as it was for 30 minutes, and then left to cool to give a vitreous form of FR173657.
Its infrared absorption spectrum and its profile in differential scanning calorimetry (DSC) were both the same as those of the vitreous form obtained in Example 1.
Vitreous form of |
15 mg | ||
Lactose | proper | ||
Croscarmellose sodium | |||
10 | |||
Hydroxypropylmethyl cellulose | |||
2 | |||
Magnesium stearate | |||
1 mg | |||
The above components were granulated and tabletted in a conventional manner to prepare bare tablets, which were coated with a film in a conventional manner to obtain film-coated tablets containing the vitreous form of FR173657.
Vitreous form of |
15 mg | ||
D-mannitol | proper quantity | ||
Low-substituted |
10 mg | ||
| |||
Crystalline cellulose | |||
20 | |||
Hydroxypropyl cellulose | |||
2 | |||
Magnesium stearate | |||
1 mg | |||
The above components were granulated and tabletted in a conventional manner to prepare bare tablets, which were coated with a film in a conventional manner to obtain film-coated tablets containing the vitreous form of FR173657.
Vitreous form of |
15 mg | ||
Lactose | proper quantity | ||
Low-substituted |
20 mg | ||
| |||
Crystalline cellulose | |||
10 | |||
Polyvinyl pyrrolidone | |||
4 | |||
Magnesium stearate | |||
1 mg | |||
The above components were granulated and tabletted in a conventional manner to prepare bare tablets, which were coated with a film in a conventional manner to give film-coated tablets containing the vitreous form of FR173657.
Solubility Test
Method
A solubility test was performed in conformity with the Japanese Pharmacopoeia(JP) XIII dissolution test, paddle method. As the test solution, 900 ml of distilled water was used. The paddle speed was set to 50 rpm. The vitreous form of FR173657 (100 g) was added to the test solution and 10 ml aliquots of the test solution were taken as samples in each measurement. Each sample was filtered through a 0.45 μm filter and analyzed by high-performance liquid chromatography.
As a control, crystal type A, crystal type B, crystal type C and a mixture of crystal types A and C of FR173657 hydrate were used.
Results
Test results are shown in FIG. 6 .
It is apparent from these results that the vitreous form of FR173657 of the invention has higher solubility any crystallographic polymorphic FR173657.
Stability Test
Stability test results of the vitreous form of FR173657 milled mechanically are shown in the following Table.
TABLE | |||||||
40° C. | 30° C. | 25° C. | |||||
| Relative | Relative | |||||
50° C. | 40° C. | humidity: 75% | humidity: 75% | humidity: 60 | |||
Initial | |||||||
3 |
3 |
3 |
3 |
3 Months | |||
Appearance | Pale | Pale | Pale | Pale | Pale | Pale |
yellowish | yellowish | yellowish | yellowish | yellowish | yellowish | |
white | white | white | white | white | white |
Form | DSC | Vitreous | Vitreous | Vitreous | Vitreous | Vitreous | Vitreous |
form | form | form | form | form | form | ||
Powder | Vitreous | Vitreous | Vitreous | Vitreous | Vitreous | Vitreous | |
X-ray | form | form | form | form | form | form |
Residual (%) | 100.0 | 101.0 | 100.8 | 101.2 | 102.1 | 102.1 |
It is apparent from these results that the vitreous form of FR173657 of the invention neither crystallizes nor decomposes at all even under heat or in moisture or through physical treatment, and is quite stable under long-term storage.
Claims (3)
1. A composition comprising:
a vitreous form of 8-[3-[N-[(E)-3-(6-acetamido-pyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6dichlorobenzyloxy]-2-methylquinoline, which is substantially free of a crystalline form thereof and which has an endothermic peak top due to glass transition at around 126 to 128° C. as determined by differential scanning calorimety (DSC; heating rate: 10° C./min) and which has an infrared absorption spectrum comprising the following peaks: 1684, 1662, 1524, 1236, and 836 cm−1; and
a pharmaceutically acceptable carrier or excipient.
2. The composition of claim 1 in the form of a tablet.
3. The composition of claim 1 in the form of granules.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/301,614 US7094899B2 (en) | 1998-10-21 | 2002-11-22 | Vitreous form of known bradykinin antagonist |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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JP29925298 | 1998-10-21 | ||
JP10/299252 | 1998-10-21 | ||
US09/807,421 US6509468B1 (en) | 1998-10-21 | 1999-10-07 | Vitreous form of known bradykinin antagonist |
PCT/JP1999/005519 WO2000023439A1 (en) | 1998-10-21 | 1999-10-07 | Vitreous form of known bradykinin antagonist |
US10/301,614 US7094899B2 (en) | 1998-10-21 | 2002-11-22 | Vitreous form of known bradykinin antagonist |
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PCT/JP1999/005519 Continuation WO2000023439A1 (en) | 1998-10-21 | 1999-10-07 | Vitreous form of known bradykinin antagonist |
US09/807,421 Continuation US6509468B1 (en) | 1998-10-21 | 1999-10-07 | Vitreous form of known bradykinin antagonist |
US09807421 Continuation | 1999-10-07 |
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US20030120076A1 US20030120076A1 (en) | 2003-06-26 |
US7094899B2 true US7094899B2 (en) | 2006-08-22 |
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US09/807,421 Expired - Fee Related US6509468B1 (en) | 1998-10-21 | 1999-10-07 | Vitreous form of known bradykinin antagonist |
US10/301,614 Expired - Fee Related US7094899B2 (en) | 1998-10-21 | 2002-11-22 | Vitreous form of known bradykinin antagonist |
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Application Number | Title | Priority Date | Filing Date |
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US09/807,421 Expired - Fee Related US6509468B1 (en) | 1998-10-21 | 1999-10-07 | Vitreous form of known bradykinin antagonist |
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US (2) | US6509468B1 (en) |
EP (1) | EP1123288A1 (en) |
JP (1) | JP3353784B2 (en) |
KR (1) | KR100419404B1 (en) |
CN (1) | CN1144801C (en) |
AR (1) | AR024220A1 (en) |
AU (1) | AU756479B2 (en) |
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IL (1) | IL142460A0 (en) |
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TR (1) | TR200101101T2 (en) |
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WO2001092254A1 (en) * | 2000-05-30 | 2001-12-06 | Fujisawa Pharmaceutical Co., Ltd. | Method for replacing organic solvents contained in clathrate crystals |
WO2003087090A2 (en) * | 2002-04-10 | 2003-10-23 | Ortho-Mcneil Pharmaceutical,Inc. | Novel heteroaryl alkylamide derivatives useful as bradykinin receptor modulators |
TWI407960B (en) | 2007-03-23 | 2013-09-11 | Jerini Ag | Small molecule bradykinin b2 receptor modulators |
SG11202004653TA (en) | 2017-11-24 | 2020-06-29 | Pharvaris Netherlands B V | Novel bradykinin b2 receptor antagonists |
AR118982A1 (en) | 2019-05-23 | 2021-11-17 | Pharvaris Gmbh | CYCLIC BRADYKININ RECEPTOR ANTAGONISTS |
UY38707A (en) | 2019-05-23 | 2020-12-31 | Pharvaris Gmbh | NEW CYCLIC ANTAGONISTS OF BRADIQUININ B2 RECEPTOR |
WO2023180577A1 (en) | 2022-03-25 | 2023-09-28 | Pharvaris Gmbh | Therapeutic uses of bradykinin b2-receptor antagonists |
WO2023180575A1 (en) | 2022-03-25 | 2023-09-28 | Pharvaris Gmbh | Solid composition comprising solubilised bradykinin b2-receptor antagonists |
TW202345810A (en) | 2022-03-25 | 2023-12-01 | 瑞士商帕法瑞斯有限責任公司 | Solid extended-release composition comprising bradykinin b2-receptor antagonists |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0622361A1 (en) * | 1993-04-28 | 1994-11-02 | Fujisawa Pharmaceutical Co., Ltd. | Heterocyclic compounds as bradykinin antagonists |
EP0662361A1 (en) | 1993-12-13 | 1995-07-12 | Hitachi Metals, Ltd. | Die casting method and die casting machine |
JPH10316677A (en) | 1997-05-19 | 1998-12-02 | Fujisawa Pharmaceut Co Ltd | Crystal |
US5958455A (en) | 1996-02-09 | 1999-09-28 | Quadrant Holdings Cambridge Ltd | Oral solid dosage forms, methods of making same and compositions thereof |
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US558455A (en) * | 1896-04-14 | Thomas lewty |
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- 1999-10-07 AU AU60043/99A patent/AU756479B2/en not_active Ceased
- 1999-10-07 TR TR2001/01101T patent/TR200101101T2/en unknown
- 1999-10-07 EP EP99970660A patent/EP1123288A1/en not_active Withdrawn
- 1999-10-12 AR ARP990105154A patent/AR024220A1/en unknown
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0622361A1 (en) * | 1993-04-28 | 1994-11-02 | Fujisawa Pharmaceutical Co., Ltd. | Heterocyclic compounds as bradykinin antagonists |
EP0662361A1 (en) | 1993-12-13 | 1995-07-12 | Hitachi Metals, Ltd. | Die casting method and die casting machine |
US5958455A (en) | 1996-02-09 | 1999-09-28 | Quadrant Holdings Cambridge Ltd | Oral solid dosage forms, methods of making same and compositions thereof |
JPH10316677A (en) | 1997-05-19 | 1998-12-02 | Fujisawa Pharmaceut Co Ltd | Crystal |
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TR200101101T2 (en) | 2001-09-21 |
CZ20011417A3 (en) | 2001-09-12 |
CN1324354A (en) | 2001-11-28 |
EP1123288A1 (en) | 2001-08-16 |
ZA200102607B (en) | 2002-07-01 |
HUP0104110A3 (en) | 2003-01-28 |
BR9914785A (en) | 2001-07-03 |
CA2347001A1 (en) | 2000-04-27 |
HK1040245A1 (en) | 2002-05-31 |
JP2002527514A (en) | 2002-08-27 |
AU6004399A (en) | 2000-05-08 |
JP3353784B2 (en) | 2002-12-03 |
US6509468B1 (en) | 2003-01-21 |
TWI230158B (en) | 2005-04-01 |
RU2202550C2 (en) | 2003-04-20 |
WO2000023439A1 (en) | 2000-04-27 |
KR20010075445A (en) | 2001-08-09 |
AU756479B2 (en) | 2003-01-16 |
IL142460A0 (en) | 2002-03-10 |
HUP0104110A2 (en) | 2002-03-28 |
CN1144801C (en) | 2004-04-07 |
KR100419404B1 (en) | 2004-02-21 |
HK1040245B (en) | 2004-10-08 |
US20030120076A1 (en) | 2003-06-26 |
AR024220A1 (en) | 2002-09-25 |
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